Continuous Subcutaneous Insulin Injection (SCII)
Medical treatment of several illnesses requires continuous drug infusion into various body compartments, such as subcutaneous and intra-venous injections. Diabetes mellitus (DM) patients, for example, require the administration of varying amounts of insulin throughout the day to control their glucose levels. In recent years, ambulatory portable insulin infusion pumps have emerged as a superior alternative to multiple daily syringe injections of insulin, initially for Type 1 diabetes patients (Diabetes Medicine 2006; 23(2):141-7) and consecutively for Type 2 diabetes patients (Diabetes Metab 2007 Apr. 30, Diabetes Obes Metab 2007 Jun. 26). These pumps, which deliver insulin at a continuous basal rate as well as in bolus volumes, were developed to liberate patients from repeated self-administered injections, and allow them to maintain a near-normal daily routine. Both basal and bolus volumes must be delivered in precise doses, according to individual prescription, since an overdose or under-dose of insulin could be fatal.
The first generation of portable infusion pumps concerns “pager-like” devices with a reservoir contained within the device's housing. These devices are provided with a long tube for delivering insulin from the pump attached to a patient's belt to a remote insertion site. Both basal and bolus volumes deliveries in these “pager-like” devices are controlled via a set of buttons provided on the device. A human interface screen is provided on the device housing for advising the user about fluid delivery status, for programming flow delivery, for alerts and alarms. Such devices are disclosed, for example, in U.S. Pat. Nos. 3,771,694, 4,657,486 and 4,498,843. These devices represent a significant improvement over multiple daily injections, but nevertheless, they all suffer from several major drawbacks, among which are the large size and weight, long delivery tubing and lack of discreetness.
To avoid the consequences of a long delivery tube, a new concept on which a second generation pumps are based, was proposed. As described in prior art, the new concept concerns a remote controlled skin adherable device with a housing having a bottom surface adapted for contact with the patient's skin, a reservoir disposed within the housing, and an injection needle adapted for communication with the reservoir. In these devices, the user interface means is configured as a separate remote control unit that contains operating buttons and screen providing fluid delivery status, programming flow delivery, alerts and alarms, as described, for example, in U.S. Pat. Nos. 5,957,895, 6,589,229, 6,740,059, 6,723,072, and 6,485,461. These second generation devices also have several limitations, such as being heavy, bulky, and expensive because the device should be replaced every 2-3 days. Another major drawback of these second generation skin adherable devices is associated with the remote controlled drug administration. The user is totally dependent on the remote control unit and cannot initiate bolus delivery or operate the device if the remote control unit is not at hand, or it is lost or malfunctions (practically, this means that the patient cannot eat).
A third generation of skin adherable infusion devices was devised to avoid the price limitation and to extend patient customization. An example of such a device was described in copending/co-owned patent applications U.S. patent application Ser. No. 11/397,115 and International Patent Application No. PCT/IL06/001276. This third generation device contains a remote control unit and a skin adherable device/patch unit that can be comprised of two parts:                Reusable part—containing the metering portion, electronics, and other relatively expensive components.        Disposable part—containing the reservoir and in some embodiments batteries.        
This concept provides a cost-effective, skin adherable infusion device and allows diverse usage such as various reservoir sizes, various needle and cannula types.
In a co-pending/co-owned International Application No. PCT/IL07/001578 and U.S. Patent Application No. PCT/IL07/001578 and U.S. patent application Ser. No. 12/004,837, claiming priority to U.S. Provisional Patent Application No. 60/876,679, a fourth generation patch unit that can be disconnected and reconnected from and to a skin adherable cradle unit was disclosed.
The fourth generation detachable skin adherable patch can be remotely controlled or can be operated by a dedicated control buttons that are located on the patch housing as disclosed in the co-owned/co-pending U.S. Provisional Patent Application No. 60/691,527 By virtue of the fourth generation patch the user can deliver a desired bolus dose by repetitive pressing of control buttons.
Continuous Glucose Monitoring (CGM)
Most diabetic patients currently measure their own glucose levels several times during the day by obtaining finger-prick capillary samples and applying the blood to a reagent strip for analysis in a portable meter. While glucose level self-monitoring has had a major impact on improving diabetes care in the last few decades, the disadvantages of this technology are substantial and consequently leading to non-compliance. Blood sampling is associated with the discomfort of multiple skin pricking, testing cannot be performed during sleeping and when the subject is occupied (e.g., during driving a motor vehicle), and intermittent testing may miss episodes of hyper- and hypoglycemia. The ideal glucose monitoring technology should therefore employ automatic and continuous testing.
Currently there are three techniques for continuously monitoring of glucose in the subcutaneous interstitial fluid (ISF):                1. The first technique is based on use of glucose oxidase based sensors as described in U.S. Pat. No. 6,360,888 to Mclvor et al. and U.S. Pat. No. 6,892,085 to Mclvor et al., both assigned to Medtronic MiniMed Inc. (CGMS, Guardian™ and CGMS Gold), and U.S. Pat. No. 6,881,551 to Heller et al., assigned to Abbott Laboratories, formerly TheraSense, Inc., (Navigator®). These sensors consist of a subcutaneously implantable, needle-type amperometric enzyme electrode, coupled with a portable logger.        2. The second technique is based on use of reverse iontophoresis-based sensors as detailed in U.S. Pat. No. 6,391,643 to Chen et al., assigned to Cygnus, Inc. (GlucoWatch™). A small current passed between two electrodes located on the skin surface draws ions and (by electro-endosmosis) glucose-containing interstitial fluid to the surface and into hydrogel pads incorporating a glucose oxidase biosensor (JAMA 1999; 282: 1839-1844).        3. The third commercial technology in current clinical use is based on microdialysis (Diab Care 2002; 25: 347-352), as detailed in U.S. Pat. No. 6,091,976 to Pfeiffer et al., assigned to Roche Diagnostics. There exists also marketable device (Menarini Diagnostics, GlucoDay™). Here, a fine, hollow dialysis fiber is implanted in the subcutaneous tissue and perfused with isotonic fluid. Glucose from the tissue diffuses into the fiber and is pumped outside the body for measurement by a glucose oxidase based electrochemical sensor. Initial reports (Diab Care 2002; 25: 347-352) show good agreement between sensor and blood glucose readings, and good stability with a one-point calibration over one day.Closed Loop Systems        
In an artificial pancreas, sometimes referred to as a “closed loop” system, an insulin pump delivers appropriate dosage of insulin according to continuous glucose monitor readings. An artificial pancreas voids human interface and is expected to eliminate debilitating episodes of hypoglycemia, particularly nighttime hypoglycemia. An intermediate step in the way to achieve a “closed loop” system is an “open loop” (or “semi-closed loop”) system also called “closed loop with meal announcement.” In this model, user intervention is required, in a way similar to using of today's insulin pumps by keying in the desired insulin before they eat a meal. A closed loop system is discussed in U.S. Pat. No. 6,558,351 to Steil et al., assigned to Medtronic MiniMed. The system is comprised of two separate devices, a glucose monitor and an insulin pump which are adherable to two remotely body sites and the loop is closed by an RF communication link. This closed loop system has some major drawbacks:                1. The glucose monitor and insulin pump are two discrete components, thus there are required two insertion sites and two skin-pricking sites for every replacement of the insulin pump and the sensor, usually every 3 days.        2. Being separated apart, the two system components should be connected either by radio communication link or by wires.        3. The pump is heavy and bulky with long tubing making the system non-discreet.        4. The system is extremely expensive because the pump infusion set and the monitor sensor should be disposed every 3 days.        